The present invention concerns a process for the production of a substituted or unsubstituted 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic from a substituted or unsubstituted 1,2-bis(4-hydroxyphenyl)-haloaliphatic. More particularly, the present invention concerns a process for the production of 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane from 1,2-bis(4-hydroxyphenyl)-2-chloropropane.
Compounds such as 4,4xe2x80x2-dihydroxy-xcex1-methylstilbenes are often useful as intermediates in the production of liquid crystal thermosets and thermoplastics. The aforementioned stilbenes are often prepared from compounds such as 1,2-bis(4-hydroxyphenyl)-2-chloropropanes. Unfortunately, however, compounds such as 1,2-bis(4-hydroxyphenyl)-2-chloropropanes must be stored in dilute concentrations at low temperatures ( less than 15xc2x0 C.) or decomposition will occur. Moreover, the process for converting the 1,2-bis(4-hydroxyphenyl)-2-chloropropane to the corresponding stilbene is disadvantageous in that hydrogen chloride, a difficult to handle co-product, is produced.
Alternate processes would be desirable in order to overcome the aforementioned problems associated with using the starting material 1,2-bis(4-hydroxyphenyl)-2-chloropropane when making stilbenes, i.e., the problems of storage and producing hydrogen chloride co-product. One alternate process would involve the dehydration of a substituted or unsubstituted 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic such as 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane. In contrast to 1,2-bis(4-hydroxyphenyl)-2-chloropropane, compounds such as 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane are often storable at ambient conditions and would only produce water as a co-product when preparing 4,4xe2x80x2-dihydroxy-xcex1-methylstilbenes. Unfortunately, however, there are no prior synthetic methods of preparing discreet compounds such as 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane.
A prior method of preparing 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane is described in Spivack, Leib and Lobos in The Journal of Biological Chemistry, Volume 269, No. 10, pages 7323-7329 (1994). The complex chemical and biological route described by Spivack et al. first involved the production of 1,2-bis(4-methoxyphenyl)-2-propanol in an unspecified yield via reaction of 4-methoxyphenyl magnesium bromide and 4-methoxyphenylacetone in dry tetrahydrofuran. Spivack et al. could not demethylate the 1,2-bis(4-methoxyphenyl)-2-propanol without substantial dehydration of the product to 4,4xe2x80x2-dihydroxy-xcex1-methylstilbene. Therefore, in order to obtain 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane Spivack et al. conducted a biochemical demethylation in the presence of the fungus, Aspergillus parasiticus. Isolation methods to recover the product from the biologic medium are not given, but are expected to be complex and to produce low yields of an impure product, based on their reported isolation of 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane as a bisphenol A metabolite in a biologic medium.
Therefore, it would be desirable to discover a synthetic process to prepare 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatics such as 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane in a simple manner with a good yield.
Advantageously, the present invention pertains to a process to prepare 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatics such as 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane in a simple manner with a good yield. The inventive process relates to producing a compound having the structural Formula I 
wherein R is independently selected from the group consisting of hydrogen, a hydrocarbyl group having from 1 to about 12 carbon atoms, a hydrocarbyloxy group having from 1 to about 12 carbon atoms, a halogen atom, and a nitro group, and R1is a hydroxyl substituted aliphatic group having from 3 to about 8 carbon atoms. The process comprises reacting a compound having the structural Formula II, 
wherein R is as described above and R2 is a halogen substituted aliphatic group having from 3 to about 8 carbon atoms with a base and water, and wherein
(1) the base is selected from the group consisting of an alkali metal carbonate, alkaline earth metal carbonate, an alkali metal bicarbonate, an alkaline earth metal bicarbonate, and mixtures thereof;
(2) the equivalent ratio of base to halogen in the aliphatic group is from about 0.9:1 to about 5:1; and
(3) the amount of water is from about 20 to about 500 percent by weight of the combined weight of the compound of Formula II and water.
The present invention also relates to novel, synthetic, compounds having structural Formula V 
wherein R is independently selected from the group consisting of hydrogen, a hydrocarbyl group having from 1 to about 12 carbon atoms, a hydrocarbyloxy group having from 1 to about 12 carbon atoms, a halogen atom, and a nitro group; R3 is an alkylene group having from 3 to about 8 carbon atoms substituted with one or more hydroxyl groups. In a particular aspect, if all R groups are hydrogen then R3 is notxe2x80x94C(CH3)(CH2OH)xe2x80x94, xe2x80x94CH2C(OH)(CH2OH)xe2x80x94, xe2x80x94C (CH2OH)(CH2OH)xe2x80x94.
As used herein, the term xe2x80x9chydrocarbylxe2x80x9d means any substituted or unsubstituted aliphatic, cycloaliphatic, aromatic, aryl substituted aliphatic, aryl substituted cycloaliphatic, aliphatic substituted aromatic, or cycloaliphatic substituted aromatic group. The aliphatic or cycloaliphatic group groups can be saturated or unsaturated. The aliphatic groups can be straight chain or branched. Suitable substituents include any substituent which does not substantially interfere with the reaction.
As used herein, the term xe2x80x9chydrocarbyloxyxe2x80x9d means a hydrocarbyl group having an oxygen linkage between it and the atom to which it is attached.
As used herein, the term xe2x80x9chydroxyl substituted aliphaticxe2x80x9d or xe2x80x9chydroxyaliphaticxe2x80x9d means an aliphatic group, such as alkylene or alkenylene, which is substituted with one or more hydroxyl groups and is divalent, i.e., has two attachment points as shown for R1 in Formula I. Similarly, the term xe2x80x9chalogen substituted aliphaticxe2x80x9d or xe2x80x9chaloaliphaticxe2x80x9d means an aliphatic group, such as alkylene or alkenylene, which is substituted with one or more halogen groups and is divalent, i.e., has two attachment points as shown for R2 in Formula II.
As used herein, the term xe2x80x9cpolar protic solventxe2x80x9d means a compound which serves as a solvent and has a high dielectric constant and strong polarity. For the purpose of the present invention, xe2x80x9cpolar protic solventxe2x80x9d means that the compound contains at least one hydroxyl group.
As used herein, the term xe2x80x9csyntheticxe2x80x9d means that the compound is prepared via a non-biological route, i.e., the compound is not prepared, for example, via bacterial metabolism.
Generally, the inventive process relates to producing a compound having the structural Formula I 
wherein R is independently selected from the group consisting of hydrogen, a hydrocarbyl group having from 1 to about 12 carbon atoms, a hydrocarbyloxy group having from 1 to about 12 carbon atoms, a halogen atom, and a nitro group, and R1 is an hydroxyl substituted aliphatic group having from 3 to about 8 carbon atoms. Preferably R is hydrogen and R1 is a hydroxyl substituted alkylene group. Preferable alkylene groups include propylene, and butylene. Preferable substituted alkylene groups include xe2x80x94C(CH3)(OH)CH2xe2x80x94 and xe2x80x94C(CH2OH)(CH2OH)xe2x80x94.
The process comprises reacting a compound having the structural Formula II with a base and water, 
wherein R is as described above and R2 is a halogen substituted aliphatic group having from 3 to about 8 carbon atoms. Preferably R is hydrogen and R2 is a halogen substituted alkylene group. Preferable alkylene groups include propylene and butylene. Preferable halogens include chlorine and bromine. Preferable substituted alkylene groups include xe2x80x94C(CH3)(X)CH2xe2x80x94 and xe2x80x94C(CH2X)(CH2X)xe2x80x94, wherein X represents xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I.
A particularly preferred embodiment is a process for producing a compound
having the structural Formula III 
by reacting a compound having the structural Formula IV 
with a base, water, and in the presence of a polar protic solvent.
The present invention also relates to novel, synthetic compounds having structural Formula V 
wherein R is independently selected from the group consisting of hydrogen, a hydrocarbyl group having from 1 to about 12 carbon atoms, a hydrocarbyloxy group having from 1 to about 12 carbon atoms, a halogen atom and a nitro group; R3 is an alkylene group having from 3 to about 8 carbon atoms substituted with one or more hydroxyl groups. In a particular aspect, if all R groups are hydrogen then R3 is not xe2x80x94C(CH3)(CH20H)xe2x80x94, xe2x80x94CH2C(OH)(CH2OH)xe2x80x94, or xe2x80x94C(CH2OH)(CH2OH)xe2x80x94.
Reaction Mixture
The starting ingredients of the present invention typically comprise a compound of Formula II, a base, and water. The compound of Formula II may be and preferably is in the form of a mixture as explained in detail below. Preferably, a polar protic solvent may also be employed.
Compound of Formula II
The starting compounds which are useful in the process of the present invention have the structural Formula II 
wherein R is as described above and R2 is a halogen substituted aliphatic group having from 3 to about 8 carbon atoms. Preferably R is hydrogen and R2 is a halogen substituted alkylene group. Preferable alkylene groups include propylene and butylene. Preferable halogens include chlorine and bromine. Preferable substituted alkylene groups include xe2x80x94C(CH3)(X)CH2xe2x80x94 and xe2x80x94C(CH2X)(CH2X)xe2x80x94 wherein X represents Cl, Br, or I.
Said compounds of structural Formula II may be employed alone or as part of a mixture. The method of preparing the compounds of Formula II is not critical. Suitable methods are described in, for example, U.S. Pat. Nos. 5,414,150; 5,475,155; 5,723,693; and 5,723,692; all of which are incorporated herein by reference in their entirety. When compounds of Formula II are prepared according to the aforementioned patents, the compounds are often obtained as a dilute, cold (15xc2x0 C. or less) mixture comprising, for example, compounds of Formula II, a phenol, an acid, minor amounts of various co-products produced in the reaction, optionally an xcex1-haloketone, and optionally a water-immiscible solvent such as, for example, methylene chloride.
A preferred mixture comprising a compound of Formula II is 1,2-bis(4-hydroxyphenyl)-2-chloropropane prepared using the methods of the aforementioned U.S. Pat. No. 5,723,692 and phenol, chloroacetone, sulfuric acid or methanesulfonic acid, and methylene chloride as reactants and a water-immiscible solvent, respectively.
If an acid is present as part of the reactant mixture, then it is often preferable to substantially remove the acid in order to facilitate the production of the desired product during the reaction. The acid may be removed by any means but often a washing of the mixture with cold water is sufficient. As described below, the acid may also be neutralized by the addition of the base to be employed in the reaction.
Base
Suitable bases or basic acting substances which can be employed as a reactant herein include any such substance or mixture of substances which hydrolyze, i.e., convert, the halogen substituted aliphatic group to a hydroxyl substituted aliphatic group. Suitable bases include, for example, the alkali metal and alkaline earth metal carbonates and or alkali metal and alkaline earth metal bicarbonates. Suitable such carbonates and bicarbonates include, for example, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, strontium carbonate, cesium carbonate, rubidium carbonate, barium carbonate including xcex1-, xcex2-, and xcex3-barium carbonate, magnesium carbonate including Mg(CO3).Mg(OH2).3H2O, 3Mg(CO3).Mg(OH2).3H2O, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium hydrogen carbonate, rubidium acid carbonate, as well as, hydrates and mixtures thereof. Preferred bases are the alkaline earth metal carbonates. Most preferred bases are magnesium carbonate, calcium carbonate, strontium carbonate, or mixtures thereof. Bases which are least preferable are those such as alkali metal hydroxides because extensive undesirable side products are produced.
The equivalent ratio of base or basic acting substance to halogen group which substitutes the aliphatic group is a sufficient ratio to obtain the desired product in the desired yield. Typically, the equivalent ratio of base to halogen is from about 0.9:1 to about 5:1, preferably from about 1:1 to about 2:1, most preferably from about 1.1:1 to about 1.5:1. The aforementioned ranges do not consider residual acid which may be present in an initial mixture comprising a compound of Formula II. If the acid is not removed or neutralized then adjustment of the aforementioned amounts of base may be desirable in order to neutralize any residual acid present in the mixture comprising a compound of Formula II. In this manner, the reaction to form the desired product is facilitated and the production of by-products is minimized.
Typically, when the equivalent ratios described above are employed, the pH of the reaction will generally be above about 5,. preferably above about 7. A pH of above about 5, preferably above about 7 is desirable in order to avoid the conversion of the compounds of Formula I to the corresponding stilbene via a dehydrochlorination or dehydration reaction. For example, if the pH falls below about 5 during the production of 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane from 1,2-bis(4-hydroxyphenyl)-2-chloropropane then 4,4xe2x80x2-dihydroxy-xcex1-methylstilbene may result. For the aforementioned reasons, if a large amount of acid is present in the initial mixture comprising Formula II, then it is preferable to substantially remove or substantially neutralize the acid such that the pH is above about 5, preferably above about 7, during the reaction to form the compounds of Formula I. One manner of neutralizing the acid is to use an amount of the base described above such that the pH of the reaction mixture is above about 5, preferably above about 7.
Water
The amount of water employed may vary depending upon the amount of water in the initial ingredients, if any, the amount of water need to suspend, partially dissolve or fully dissolve the base, and other such variables. However, typically water is employed in an amount of from about 20 to about 500, preferably from about 40 to about 300, most preferably from about 60 to about 150 percent by weight of the combined weight of the compound of Formula II and water. The aforementioned quantities of water are the quantities necessary in order for the water to serve as a reactant and a reaction medium. If, for example, a less water-soluble base is employed then additional water may be necessary. Stirring or mixing is often desirable while adding water, and during the reaction. In this manner, complete dispersion of the water and even heating of the reactants is facilitated.
Polar Protic Solvent
The polar protic solvent is not critical for the process of the present invention but is often preferred depending on the starting ingredients and other parameters which are to be employed. The polar protic solvents useful herein include, for example, aliphatic alcohols, glycols, glycol ethers, and mixtures thereof. Such solvents include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, t-amyl alcohol, ethylene glycol, ethylene glycol monomethylether, ethylene glycol monoethylether, propylene glycol monomethylether, as well as, mixtures thereof. More preferred polar protic solvents include ethanol, n-propanol and isopropanol, with ethanol and isopropanol being most preferred.
The amount of polar protic solvent used, if any, varies depending upon the amount of water used, the need to suspend, partially dissolve or fully dissolve the basic acting substance, the dispersion of reactants, and other such variables. Typically, the polar protic solvent is used in an amount of less than about 500, preferably from about 50 to about 300, most preferably from about 75 to about 150 percent by weight of the combined weight of the compound of Formula II and polar protic solvent used. The polar protic solvent, if used, often serves as a medium for the hydrolysis reaction, solvates the product preventing its premature precipitation, and/or modifies the dispersion of the various reactants, for example, inducing formation of a single phase reaction mixture versus a two-phase reaction mixture.
Process
The process of the present invention may be conducted as a continuous or batch process. Similarly, many different atmospheres may be employed, however, it is often preferable to conduct the reaction in an inert atmosphere such as nitrogen.
In the process of the present invention, the compound of Formula I, alone or in a mixture, is reacted with a base and water. As described above, a polar protic solvent may also be employed.
While the ingredients may be mixed together in any order, it is often preferable to first mix the base, water and, optionally, the polar protic solvent at ambient conditions. The mixture comprising base, water, and, optionally, solvent may then be heated to the desired reaction temperature which is described below. The compound of Formula II or mixture comprising a compound of Formula II is then added either incrementally or in bulk to the mixture comprising base, water, and, optionally, solvent, while a desirable reaction temperature is reached and maintained until the substantial completion of the reaction. During the reaction, mixing or stirring is often desirable to assure an even temperature of the reaction mixture and complete dispersion of the reactants.
Suitable temperatures, pressures, and times of the reaction often vary depending upon the starting ingredients. The reaction may be conducted at atmospheric, reduced, or increased pressure, but it is often advantageous to employ a temperature and pressure at which the starting ingredients are in a liquid form, i.e., the temperature and pressure are not such that one or more ingredients freezes or boils. In this manner, the ingredients are easily measured and metered into the reaction vessel.
Preferably, the reaction is conducted at atmospheric pressure at a temperature of from about 0xc2x0 C. to about 100xc2x0 C., preferably from about 25xc2x0 C. to about 80xc2x0 C., more preferably from about 40xc2x0 C. to about 70xc2x0 C.
The reaction time will vary depending upon the starting ingredients, pressure, temperature, solubility of the base and other such variables. Typically, the reaction mixture is maintained at the reaction temperature for a sufficient time to hydrolyze, i.e., convert, the halogen substituted aliphatic group to a hydroxyl substituted aliphatic group. Generally, the higher the reaction temperature is, the shorter the period of time that the reaction requires. Correspondingly, the lower the reaction temperature is, the longer the period of time that the reaction requires.
At atmospheric pressure and temperatures of from about 0xc2x0 C. to about 100xc2x0 C., the reaction time is typically from about 30 minutes to about 48 hours, preferably from about 60 minutes to about 24 hours, more preferably from about 2 hours to about 12 hours.
In the process of the present invention, it is typically desirable to choose a reaction time and temperature profile and a manner of contacting the ingredients together which provides the greatest conversion and selectivity of the desired compound of Formula I. Thus, it is frequently of value to conduct simple preliminary experiments over the range of variables which can be employed in order to define an optimum reaction time, temperature, and manner of contacting the ingredients which provides the greatest conversion and selectivity to the desired compound of Formula I. In this manner, conditions are obtained which are conducive to optimizing the yield of the desired compound of Formula I which is substantially free of unwanted coproducts.
In the preliminary experiments and the process of the present invention, it is frequently desirable to monitor the course of the reaction via an analytical method, such as high pressure liquid chromatographic analysis (HPLC).
During the course of the reaction, water-immiscible solvents such as methylene chloride may be introduced into the reaction product via an original mixture comprising a compound of Formula II. It is preferable to allow such water-immiscible solvent or solvents, if present in large amounts, to evaporate or distill from the stirred, heated mixture during the course of the reaction and after the reaction. This distillation may be assisted by the application of a gentle vacuum during the reaction, although care must be taken not to remove other ingredients from the reaction mixture, i.e., compounds of Formula II, bases, water, or optional polar protic solvents.
Recovery of the Product
The recovery of the compounds of Formula I from the reaction product should be performed using conditions and methods which preserve the majority of the product. Thus, evaporation, distillation, vacuum distillation, rotary evaporation, falling film distillation, wiped film distillation, or other such methods may be advantageously employed to remove volatile materials, such as, for example, phenol-water azeotrope, any residual water-immiscible solvent, and polar protic solvent.
When employing azeotropic distillation it is often preferred to use a reduced pressure. In the course of such azeotropic distillation, water may be added or removed from the reaction product, as needed, to facilitate recovery and isolation of the compound of Formula I. The presence of water often serves to assist azeotropic removal of phenols which may be introduced into the reaction product via an original mixture comprising a compound of Formula II. The azeotropic removal of phenol under aqueous conditions typically induces precipitation of the 1,2-bis(4-hydroxyphenyl)-2-hydroxypropane as a crystalline product. Thus, recovery of the product is facilitated.
The amount of water employed in the course of azeotropic distillation may vary depending upon the amount of the phenol present, the structure of the phenol present, the amount of water used in the reaction, and other such variables. Typically, water is employed during azeotropic distillation in an amount of from about 10 to about 500, preferably from about 25 to about 300, most preferably from about 50 to about 200 percent by weight of the combined weight of the reaction product and water.
For certain reaction products, wherein minor amounts of co-products are present, it is frequently advantageous to leave a minor amount of phenol in the aqueous crystalline slurry as a solvent for said coproducts. The crystalline compounds of Formula I may be recovered from aqueous slurry using any unit operations which effectively remove the crystals from said slurry, such as, for example, filtration or centrifugation followed by water washing to remove any salts. It is frequently useful to conduct simple preliminary experiments over the range of time and temperature at which the crystalline slurry can be held in order to define an optimum time and temperature profile which provides the greatest isolated yield of the desired compound of Formula I.
The compound of Formula I, once isolated, is advantageously maintained as a wet product stored at a reduced temperature to avoid decomposition. The recovered product may be utilized as a wet cake, or dried, for example under vacuum at temperatures which are not deleterious to said product, typically below 30xc2x0 C. The compounds of Formula I may be converted to, for example, stilbenes by any suitable method. Suitable methods include those described in U.S. Pat. Nos. 5,414,150; 5,475,155; 5,723,693; and 5,723,692; all of which are incorporated herein by reference in their entirety.
Conversion to Stilbene
In the process of the present invention wherein a substituted or unsubstituted 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic is converted to the corresponding stilbene compound, any protic acid, Lewis acid, or mixture thereof may be employed to catalyze the dehydration reaction. Such acids are defined and examples listed in the patent references previously mentioned and incorporated herein by reference. Examples of additional such acids include sodium hydrogen sulfate, potassium hydrogen sulfate, acetic acid, phosphoric acid, phosphorous acid, sulfurous acid, trichloroacetic acid, and trifluoroacetic acid. Also, simple heating of the neat 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic to temperatures in excess of about 30xc2x0 C. can induce conversion to the corresponding stilbene compound, due to the presence of trace acidic components, such as sulfonic acid(s), sulfuric acid, alkanesulfonic acid(s), hydrochloric acid, mixtures thereof and the like, all or some of which may be present in the 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic depending on it""s synthetic history. Additionally, trace amounts of halogen-containing coproducts which may be present in the 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic, may serve as a source of hydrogen halide upon heating.
Because of the concomitant formation of substantial amounts of dimeric coproducts in the dehydration reaction of neat 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic, it is more preferred to conduct the reaction in one or more solvents, such as, for example, water, polar protic solvents, or mixtures thereof and the like. Said solvents are useful to dissolve the acid catalyst and assist its transfer in the reaction medium, to dissolve or suspend the 1,2-bis(4-hydroxyphenyl)-hydroxyaliphatic, and to provide dilution needed to minimize formation of dimeric coproducts. Most preferred are the solvents and reaction conditions given for the dehydrohalogenation reaction of 1,2-bis(4-hydroxyphenyl)-haloaliphatics in the patent references previously mentioned and incorporated herein by reference, especially those found in U.S. Pat. No. 5,723,692.